The principal objective of this project is to characterize the consequences of signal transduction mediated by HIV and/or its products as they relate to HIV replication and immune dysfunction. HIV envelope proteins induce a number of biological responses in primary T-cells and macrophages including the induction of expression of proinflammatory cytokines and increased rates of apoptosis. Elucidation of the complexities and significance of the signaling processes that HIV-1 envelope induce may substantially enhance our understanding of HIV-1 pathogenesis, and perhaps facilitate the discovery of new strategies for the treatment of and immune response to HIV infection. Because envelopes vary with respect to their co-receptor usage and tropism, a panel of envelopes that encompass those viral phenotypes ascribed to the envelope was developed. This panel includes both CCR5 and CXCR4-specific envelopes. Envelopes representing each of the five major sub-types of HIV were generated, as well as different subtypes of SIV envelopes.We employed those recombinant gp120 proteins to treat primary PBMCs as well as macrophages. High-density oligonucleotide microarray analysis and high throughput Western Blot analysis was used to characterize the complex response to envelope-mediated signaling. HIV envelope induced the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation. Transcriptional changes that were observed included an upregulation of NFAT, induction of the RNA polymerase II complex including TFII D and certain plasma membrane associated proteins including several syntaxins, and members of the Rho protein family, including Cdc 42. Of note, these events occurred in the absence of cellular proliferation. It is possible that gp120-mediated effects increase the susceptibility of target cells to productive infection and may contribute to the low level replication of HIV in cells that do not express markers of activation. Replication in this manner may contribute to the establishment and maintenance of reservoirs of HIV infection. In agreement with the microarray data we show that HIV envelope induces the expression of HIV from resting CD4+ T cells of HIV-infected patients in the absence of induction of markers of classical T cell activation. Recombinant trimeric HIV envelope protein induced the expression of HIV from resting (CD25-CD69-HLA-DR-, non-dividing) CD4+ T cells isolated from HIV-infected individuals. Envelope protein from both CCR5 and CXCR4 HIV strains induced replication competent HIV. These data suggest that HIV virions or free envelope protein induced a level of cellular stimulation that is sufficient for HIV expression, but that is below the threshold required for classic T cell activation. Furthermore, this model suggests that HIV may propagate itself in non-dividing cells that have an inherently longer half-life than do classically activated T cells.